Specific Topic: #20. Basic Underlying Mechanisms of Musculoskeletal Aging Skeletal aging is characterized by bone loss resulting in high risk of fracture in osteoporosis patients. The mechanisms for skeletal aging are not entirely clear, but likely relate to decreased availability of bone growth factors. Recent human genetic study demonstrated that osteoporosis is associated with the polymorphisms of BMP-2 gene. Animal studies have also indicated that an age-related decline of BMP-2 expression and function may account for one of the molecular pathogenic mechanisms of age-related osteopenia. But, how BMP-2 gene expression is regulated, especially in skeletal aging, is not well understood. Recent genetic studies have shown that the transcription factor Gli2 in Shh signaling pathway plays important roles in skeletal development. In our preliminary studies, we have found that Gli2 has dramatic stimulating effects on BMP-2 gene expression and osteoblast differentiation. Our hypothesis is that Gli2 is a powerful regulator for the BMP-2 gene expression and consequent postnatal bone formation, and plays important roles in skeletal aging. This proposal will identify the molecular mechanisms by which Gli2 stimulates BMP-2 gene expression and characterize the age-related effects of Gli2 on the regulation of BMP-2 expression and consequent bone formation. Two specific aims are proposed. First, we will explore the molecular mechanisms of Gli2 transactivation on BMP-2 gene by loss-of-function studies and the protein/DNA interaction. Secondly, we will determine the roles of Gli2 in age-related BMP-2 regulation and skeletal aging through characterizing tissue specific Gli2 transgenic mice. We believe that full characterization of the roles of Gli2 in BMP-2 gene regulation and postnatal bone formation will lead to insights into the molecular mechanisms of bone anabolic regulation especially in age-related bone biology, and provide a potential target for the treatment of clinical senile ostoepenia.